The present invention relates generally to peritoneal dialysis. More specifically, the present invention relates to peritoneal dialysis solutions.
It is known to use dialysis to support a patient whose renal function has decreased to the point where the kidneys no longer sufficiently function. Two principal methods of dialysis are utilized: hemodialysis; and peritoneal dialysis. Hemodialysis utilizes an artificial kidney dialysis machine through which the patient's blood is passed. A membrane in the machine acts as an artificial kidney and cleanses the blood. Hemodialysis is an extracorporeal treatment that requires special machinery. Therefore, there are certain inherent disadvantages with hemodialysis.
Peritoneal dialysis was developed to overcome some of the disadvantages associated with hemodialysis. In peritoneal dialysis, a patient's own peritoneum is used as a semi-permeable membrane. The peritoneum is capable of acting as a natural semi-permeable membrane due to the large number of blood vessels and capillaries present in this membranous lining of the body cavity.
In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. By providing a suitable osmotic gradient from blood to dialysate, fluid removal is achieved permitting water outflow from the blood. This allows the proper acid-base, electrolyte and fluid balance to be returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter.
There are many advantages to peritoneal dialysis. However, one of the difficulties that has been encountered is providing a dialysate that includes a suitable osmotic agent. What is required is that a sufficient osmotic gradient is achieved. To achieve the osmotic gradient, an osmotic agent is used. The osmotic agent maintains the osmotic gradient required to cause transport of water and toxic substances across the peritoneum into the dialysis solution.
In order to be suitable, the osmotic agent needs to achieve at least a couple of criteria. First, it needs to be non-toxic and substantially biologically inert. However, the agent should be metabolizable. The agent should not rapidly cross the peritoneum membrane into the blood. By achieving both these criteria, one is able to allow maintenance of the maximum ultrafiltration gradient, and also prevent toxicity or accumulation of unwanted substances in the blood.
It is believed that no currently used substances currently satisfy the criteria for an osmotic agent in a dialysis solution. The most widely used osmotic agent today is dextrose. Dextrose is fairly safe and is readily metabolizable if it enters the blood.
But, one of the problems encountered with dextrose is that it is rapidly taken up by the blood from the dialysate. Because dextrose crosses the peritoneum so rapidly, the osmotic gradient is dissipated within two to three hours of infusion. This can cause reversal of the direction of ultrafiltration, causing water to be reabsorbed from the dialysate toward the end of the time allowed for the exchange.
A further concern with respect to dextrose is that because it is taken up so rapidly by the blood, it can represent a large proportion of the patient's energy intake. In non-diabetic patients, this may not be significant. However, this can represent a severe metabolic burden to a patient whose glucose tolerance is already impaired. Dextrose can also cause problems with respect to patients having hyperglycemia or who are obese.
A further problem experienced with dextrose is with respect to the preparation of a dialysis solution. Dialysis solutions, similar to other medical products and solutions, are typically sterilized by heating. Unfortunately, heat sterilization of dextrose at physiological pHs will cause dextrose to caramelize. To compensate for this problem, it is known to adjust the pH of the dialysate to within the range of 5 to 5.5--at this low pH, dextrose caramelization will be minimal when heated. However, it is believed that this low pH may be responsible for the pain some patients experience on the in-flow of dialysis solution. Additionally, the low pH of the solution may cause other problems, e.g., may effect peritoneal host defense.
To address some of the above concerns, a number of substances have been proposed as alternatives to dextrose. It is believed that none of the proposed materials currently available have proven to be an adequate substitute for dextrose.
Dextrans, polyanions, and glucose polymers have been suggested as replacements for dextrose. Because of their high molecular weight, it is believed that their diffusion across the peritoneum and into the blood should be minimized. But, the low osmotic activity per unit mass of these materials dictates the need for larger concentrations (w/v) of these materials in the dialysis fluids in order for them to be effective. Additionally, systemic absorption of these materials, mainly through the lymphatics, along with slow metabolism, raises serious concerns about the long term safety of these agents.
Small molecular weight substances have also been explored. These substances include glycerol, sorbitol, xylitol, and fructose. However, these substances are believed to raise a number of safety concerns while offering no substantial advantage over dextrose.
An attractive substitute for dextrose appears to be amino acids. Short term studies have indicated that amino acids are well tolerated. But, because of their low molecular weights, they are transported quite rapidly through the peritoneum resulting in a rapid loss of osmotic gradient. Additionally, the rapid uptake of amino acids leads to a considerable nitrogen burden and limits the use of amino acids to one to two exchanges per day.
Recently, polypeptides have been explored as a potential class of osmotic agents. It is believed that polypeptides will have a slow transport across the peritoneum and therefore maintain a prolonged osmotic gradient between the dialysate and blood. U.S. Pat. No. 4,906,616 to Gilchrist et al and European Patent No. 0218900 to Klein set forth polypeptides as the osmotic agent in the peritoneal dialysis solution. Each of these patents discusses the substitution of polypeptides for dextrose. As disclosed, polypeptides are the only osmotic agents utilized in these formulations.
It is believed that the polypeptide solutions proposed by Klein and Gilchrist et al have very limited clinical use. Although larger in size, like amino acids, these polypeptide compositions are absorbed from the peritoneum quite rapidly. This leads to uremic symptoms. In addition, these materials containing polypeptides have the potential of producing allergic reactions. This is due to the size of polypeptides that are used.
Glucose polymers have also been explored in peritoneal dialysis solutions. U.S. Pat. No. 4,761,237 discloses the use of glucose polymers in a dialysis solution. EP 0 076 355 discloses a dialysis solution comprising the conventional electrolyte combination of sodium, calcium, magnesium, chloride, lactate, and sodium hydroxide with the alleged improvement comprising the use of a glucose polymer as the osmotic agent. EP 0 153 164 discloses a peritoneal dialysis solution having an osmotic agent that is a glucose polymer mixture. U.S. Pat. No. 4,886,789 is believed to relate to EP 0 153 164.
It is believed that the disclosed solutions do not overcome all of the issues set forth above.
There is therefore a need for an improved peritoneal dialysis solution.